Battling to save kids’ lives – and ethics of research

A team of scientists faced a tough question: what caused children’s deaths in Bihar’s litchi belt. Once they cracked the puzzle, they faced an even tougher one

sreelatha

Sreelatha Menon | January 25, 2016


#Litchi   #Bihar children   #Bihar death   #T Jacob John  


A team of Indian scientists is in a quest for truth – though it is a different kind of quest they are on this time. And it is threatening to turn as venomous as the deadly substance they have found in the divinely sweet interior of the litchi fruit – for which discovery, another team is claiming the credit.

The story began in 2013 when, faced with recurrent deaths of children due to a mysterious brain disease in litchi-harvesting belts of Muzaffarpur, the Bihar government and the health ministry of the central government turned to veteran virologist Dr T Jacob John. They could not have got a better expert: Dr John, since his MBBS way back in 1958, followed by a PhD in 1976, has a long and distinguished career in public health. In a way, he was the brain behind the polio vaccination campaign.

What could be the cause of deaths? The prime suspect was some yet-to-be-identified virus. The next suspect was the fruit itself, that is, some substance in it – it could be a toxin in litchi or something in the pesticide used. Other suspects were bats which were eating litchis and hence probably passing on some disease to children who ate the bat-eaten litchis. The common factor to all deaths was that the children were dying in the litchi-belt during the litchi harvesting season of May and June, recalls Dr John.

He camped at Muzaffarpur, met villagers and began his work. He ruled out the virus angle and was zeroing in on a chemical within litchi. “A similar disease was caused by another fruit called ackee that belongs to the same plant family as litchi. This disease was metabolic and was called hypoglycaemic encephalopathy, or ‘Jamaican vomiting sickness’. So I was able to rule out virus in the very beginning,” he says.

“Ethical scientists will not claim credit of someone else’s research”

An interview with Dr T Jacob John

A Google search shows both your papers, and the authors of the CDC report couldn’t have missed it. Why would they do it?
That is what we said in the Current Science letter. Our suspicion was that they might have wanted to appear as the first to diagnose hypoglycemic encephalopathy and to propose MCPG mediation to explain litchi association, while we had already published such information. With that guess we wrote to the journal the letter wondering if they committed misconduct.

You were working with government and the other group of researchers was also working with government bodies. So how come the two groups never communicated?
In 2013, after I made the diagnosis of encephalopathy and categorically refuted encephalitis, I was very open with government officers and paediatric colleagues. So other group knew about my conclusions – such as the SK Medical College faculty, doctors of the Kejariwal maternity and child hospital in Muzaffarpur, AIIMS professors in Patna and regional medical research centre personnel. NCDC officers had been coming repeatedly for a few or even several years to investigate; in fact, their earliest known investigation was in 1995.

Some research reports were already in medical journals. The point is, there was no unified line of command or communication – each group had some hypothesis and supporting arguments. CDC investigators had made a presentation in Patna in 2013, stating that the disease could be encephalitis or could be encephalopathy and that both lines will be investigated by them.

In other words, we all knew what each group was doing and what they were reporting. When I spoke to the health secretary and the executive director of NRHM they clearly responded that this concept (encephalopathy and hypoglycin) was new to them. The idea that children should not be fasting overnight came from such discussions. The risk factors of undernutrition and ‘possible prolonged fasting’ were already identified as amenable to intervention.

I had held press meets in Patna and Muzaffarpur in 2014. All details were shared and there were press reports; I did not keep any [secrets].

Wouldn’t the Indian government bodies have known it, if not CDC?
All Bihar government officials concerned with health, the district medical officer of Muzaffarpur and the district magistrate – all knew since I had met them individually. In 2014 I took classes for all 32 PHC medical officers of Muzaffarpur district teaching them how to collect blood for glucose estimation and immediately infuse 10 percent dextrose.

Does CDC normally get into research in India? Won’t it be a welcome thing?
CDC has a presence in NCDC and that is a very good thing as CDC is the Mecca of disease investigations, epidemiology and control. What they do is not to be considered as research but their role is to train the Indian staff in NCDC on disease investigations.

The issue of who is in charge of outbreak investigations is confusing. Who is in charge – the centre or the state? There was a task force on encephalitis in Bihar and as far as I know, NCDC and CDC were not getting all players together and working as one team. Such a directive ought to come from the government – but the centre or the state? I am not clear myself.

Are you upset about the incident?
On the contrary, I am very pleased to have been able to make a precise clinical diagnosis, prove it and propose the agent that triggers it. My team included a toxicology expert (Mukul Das) from the Indian Institute of Toxicology Research in Lucknow and a local paediatrician (Arun Shah). I had an excellent pathology colleague (Dr Nabeen Nayak of Gangaram hospital, Delhi) standby – but I could not get tissues for testing.

NCDC and CDC scientists writing in MMWR without acknowledging our work and precedence or originality is not appreciated in science in which we seek truth and the means should be completely honest. Scientists should give credit for being first. Ethical scientists will not claim credit of someone else’s ‘first’.

We continue to have a march ahead of NCDC, CDC and every other group since we postulated, and predicted MCPG and finally proved its presence in the fruit pulp. So ultimately Indian scientists have shown that we have skill and expertise, whether governments understand or not. I must add it was the Bihar government who invited me – I guess out of exasperation, since scientists were investigating the matter since 1995 but not solving it and not giving specific methods of interventions – to save lives after onset of illness and to prevent children falling ill with hypoglycemic encephalopathy. We have provided both.


His hunch was that it was worth looking for a toxin within the fruit. He suggested this in a report in May 2014 – in the leading journal of its kind in India, Current Science, published by the Current Science Association in collaboration with the Indian Academy of Sciences. He and his co-researcher, Mukul Das, wrote:
“In animal experiments, MCPA (the hypoglycin found in ackee) and MCPG (the hypoglycin in litchi) have been shown to induce encephalopathy and hypoglycaemia. Encephalopathy is explained by the mitochondrial inhibition of fatty acid-oxidation and accumulation of toxic metabolites. Our hypothesis is that the Muzaffarpur AES is caused by MCPG in lychee. However, we do not know if it is present only in the seed or also in the edible fruit flesh and if unripe lychee has more MCPG than ripe fruits.”
Their conclusion: “…tightly  estricted seasonality and geographic distribution as well as sparing of children below 2 years support the diagnosis of acute non-infectious encephalopathy as against viral encephalitis.”

In September 2014, doctors John, Das and Arun Shah published further findings on the toxin hypothesis in the same journal.
They, however, were in for a shock when they found the same findings reproduced in an American journal a few months later – without any credit, acknowledgement or reference to their research.

Akash Srivastava, who is with the National Centre for Disease Control of the health ministry, along with a team of researchers published this set of findings in the Morbidity and Mortality Weekly Report (MMWR), a journal published by the Centers for Disease Control and Prevention (CDC) of the US government. The March 2015 report arrived at the same conclusion, that the brain disease among children in Muzaffarpur was not caused by a virus but by some toxin within litchi seeds or fruit, and the condition was hence not a viral disease but a metabolic disorder called hypoglycaemic encephalopathy.

Dr John and his co-authors took up the matter in a letter published in Current Science in September 2015. It asked: “Publishing on hypoglycemic encephalopathy, borrowing information without giving credit: Is Current Science invisible?”

They noted, “Annual seasonal outbreaks of what was popularly called acute encephalitis syndrome in Muzaffarpur, Bihar were clinically diagnosed in 2013 by us as non-infectious, toxic, hypoglycemic encephalopathy... The toxin was pinpointed as methylenecyclopropylglycine (MCPG). Thus, our first publication in May 2014 in Current Science was a breakthrough after many groups of investigators had failed for many years to diagnose the disease or provide any plausible causative associations.

“In 2014, we confirmed with clinical evidences that the disease is indeed hypoglycemic encephalopathy and the patients could be saved with prompt correction of hypoglycemia. These results were published, again in Current Science, in August 2014.” But in January 2015, MMWR came out with a report by a large group of investigators, stating that the disease is acute hypoglycemic encephalopathy with putative association with litchi, as if they were the first to arrive at such a conclusion.”

“Our 2013 investigations which appeared in May 2014 in Current Science were a watershed. But the studies of Shrivastava et al published in January 2015 in MMWR have not cited our earlier contributions – one reason could be that Current Science is invisible in the usual biomedical literature surveys. However, when we conducted a simple literature search through a popular search engine, we found references to both our papers.”

How we solved Muzaffarpur’s mystery malady

Dr T Jacob John narrates how he and his team of health investigators cracked down the cause of the mystery disease that has been killing children in Bihar. Their quest ended with finding a toxin in litchi

Every year, during May and June, large number of children fall ill with an acute brain disease, and many of them die, in Muzaffarpur district. Until a few years ago the disease was called encephalitis, assuming it to be due to some viral infection. Tests for the Japanese encephalitis virus infection had been negative. Teams sent by the union government had tested for all other potentially encephalitis-causing viruses over several years and all tests were negative. This gave rise to the popular term ‘mystery disease’ and the medical term ‘acute encephalitis syndrome’ (AES) – meaning encephalitis of unknown causation.

Most sick children are brought to the medical college or to a charitable mother-and-child hospital in Muzaffarpur city. They opened ‘encephalitis wards’ to admit and treat the influx of children with AES.

In 2013, I was requested to assess the situation by health ministry officials and I camped in Muzaffarpur and examined ill children, interviewed doctors and parents, visited the villages from where children had come, visited families of children affected in the previous years and their neighbours. Some clear facts emerged:

  • Medically, the disease did not have any evidence of brain inflammation to deserve the term encephalitis. On the other hand, it appeared to fit with a metabolic disease, in which brain is not the primary site of pathology. Such diseases are called ‘encephalopathy’.
  • Many children had low blood sugar values supporting the metabolic pathway of disease causation. Thus the disease fitted the general term ‘hypoglycemic encephalopathy’.
  • All children with the seasonal brain disease were visibly undernourished. Doctors were clear: no well-nourished child ever got the Muzaffarpur encephalopathy.
  • Only rural children were affected. The affected villages were thick with litchi orchards; many children came from litchi-harvesting families. May and June are the litchi-harvesting months.
  • Litchi fruits are harvested early in the morning. Only bunched fruits are valued; any single fruits that fall to the ground had no commercial value and children could hoard them. Thus children have ready access to litchi fruits.
  • The hypoglycemic encephalopathy always started between 4 am and 8 am; no case occurred outside this interval. Normally, this is the time when blood sugar dips and liver pumps out glucose to keep the brain cells constantly supplied with energy. Undernourished children would have little or no store in the liver and are vulnerable to hypoglycemia.
  • The disease was not simply low blood sugar and consequent unconsciousness – children had signs of brain cell damage, by way of seizures, muscle tone showing rigidity, and children who had survived had gross signs of brain damage. Thus, malnutrition alone did not explain why an occasional child in a village got sick but not others. An external toxin was suspected – pesticides? The disease did not have similarities to any pesticide poisoning.
  • A Jamaican fruit called ackee causes a hypoglycemic encephalopathy in children; the reason is the presence of a chemical, generally called ‘hypoglycin’. Ackee and litchi belong to the same plant family. I contacted Dr Mukul Das, a renowned toxicologist with the Indian Institute of Toxicology Research (IITR), Lucknow, and he found that in 1962 some European toxicologists had detected hypoglycin in litchi seeds collected from an East Asian country.
  • We informed health ministry officials all these details and proposed a hypothesis; recommended both further studies and some interim specific interventions, as follows.
The hypothesis was: stressed with the need for glucose in the blood but without glucose store in the liver, the well-known alternate pathway to produce glucose would kick in. That is called ‘fatty acid oxidation’ which results in glucose being synthesized de novo. Ackee hypoglycin blocks that metabolic pathway and the blocked biochemistry results in accumulation of chemical moieties that are toxic to brain cells. So our hypothesis was that a similar metabolic block would be caused by litchi hypoglycin, if it actually existed in the edible part of litchi fruit.

In 2014, with the help of Dr Arun Shah of Muzaffarpur, we confirmed that the disease was definitely hypoglycemic encephalopathy.

Children would not swallow seeds. Hence, litchi fruits should be tested for the presence of hypoglycin. Also sick children should be tested for the presence of the chemical moieties, for which some specific biochemistry tests were recommended.

Meanwhile, we recommended that the health staff should teach the community that no child should go to bed without a ‘cooked meal’ not to face the risk of hypoglycemia. Parents were to supervise children eating litchi, especially in the evenings. These recommendations were instituted by the ministry officials. All primary health centre (PHC) doctors were taught to infuse glucose early in the course of illness so as to mitigate the need for fatty acid oxidation. The one missing link was: does litchi fruit (edible pulp) contain the hypoglycin? With the help of Dr Shah litchi fruits were collected, both semi-ripe and fully ripe, in 2014 and tested in IITR by Dr Das and his team in 2015.

As previously described, seeds contain the hypoglycin in large concentration. We found that semi-ripe and fully ripe fruits also contain the hypoglycin, more in semi-ripe than in the fully ripe fruit pulp.

 


When Governance Now contacted  MMWR, its executive editor Charlotte Kent replied promptly on December 2 saying that matter would be investigated. “We received your two emails from today about the MMWR report, “Outbreaks of Unexplained Neurologic Illness – Muzaffapur, India, 2013-14”. We are planning on investigating the concern you raised,” she said in an email. MMWR has not sent any further information on the matter since then. Srivastava, meanwhile, did not reply to the emailed queries.

Several questions are raised by this incident, especially since the parallel research published by CDC was also done with help of Indian government bodies.

Dr John also rues the fact that this episode pits Indian scientists against each other. He says that ultimately it proves that Indians can do their research and reach the truth without external help. However, he adds that distortion of truth does leave a bitter taste in the mouth and is just not done in science.

An ethical scientist would not claim credit for someone else’s work, says the veteran virologist.

 

 

(The story appears in the January 16-31, 2016 issue)
 

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